Aromatase Inhibitors in Pulmonary Vascular Complications of Liver Disease

芳香酶抑制剂治疗肝病肺血管并发症

• 批准号: 8499401
• 负责人: Steven M Kawut
• 金额: $ 19.38万
• 依托单位: UNIVERSITY OF PENNSYLVANIA
• 依托单位国家: 美国
• 财政年份: 2011
• 资助国家: 美国
• 起止时间: 2011-05-01 至 2016-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8499401
• 关键词: Adverse effects; Affect; Alveolar; Area; Aromatase; Aromatase Inhibitors; Attention; Award; Basic Science; Biochemical; Biometry; Blood Vessels; Cardiovascular system; Cessation of life; Cirrhosis; Clinical; Clinical Research; Clinical Trials; Collaborations; Commit; Critical Care; Data; Development; Disease; Environment; Epidemiology; Estradiol; Estrogen Receptors; Estrogens; FDA approved; Female; Fostering; Funding; Future; Gases; Gender; Genetic Determinism; Genetic Variation; Goals; Growth; Head; Hepatology; Hepatopulmonary Syndrome; Housing; Hypersensitivity; Hypertension; Hypertrophy; Industry; Institutes; Laboratories; Liver; Liver diseases; Lung; Measures; Medial; Mediator of activation protein; Medical; Medicine; Mentors; Mentorship; Methodology; Morbidity - disease rate; Muscle; Oxygen; Patient Care; Patients; Pennsylvania; Peripheral; Phase; Physiological; Placebos; Plasma; Portal Hypertension; Postmenopause; Prevention; Production; Publications; Pulmonary Hypertension; Pulmonary artery structure; Randomized Clinical Trials; Rare Diseases; Research; Research Personnel; Resources; Right Ventricular Dysfunction; Risk; Risk Factors; Safety; Signal Transduction; Time; Training; United States National Institutes of Health; Universities; Vascular Diseases; Walking; Woman; alternative treatment; anastrozole; base; career; clinical epidemiology; design; functional status; high risk; interest; liver transplantation; malignant breast neoplasm; medical schools; medical specialties; men; mortality; neglect; novel therapeutics; patient oriented research; patient population; prevent; professor; programs; pulmonary arterial hypertension; research study; screening; skills; success; therapeutic target; treatment strategy

Steven M. Kawut, MD, MS is an Associate Professor of Medicine and Epidemiology at the University of Pennsylvania School of Medicine (Penn) who has committed his career to the research and care of patients with pulmonary vascular disease (PVD). His interest in this area began early in his training and has guided his development since then. He heads a federally-funded research program based on the epidemiology and treatment of PVD and right ventricular dysfunction. He has also mentored more than twenty-nine trainees to success in patient-oriented research (POR), resulting in publications and funding as they develop towards their own independence. Dr. Kawut¿s recent recruitment to Penn to direct the Pulmonary Vascular Disease Program has created a significant opportunity to expand his research program as well as to train and mentor young investigators. There are outstanding resources at Penn housed in the Cardiovascular Institute, the Pulmonary, Allergy, and Critical Care Division, and the Center for Clinical Epidemiology and Biostatistics available to the candidate and his trainees. These include state-of-the-art clinical research and laboratory resources. The candidate¿s immediate- and long-term career goals during this award center on acquiring skills in performing clinical trials in rare PVDs and developing his mentorship abilities. The environment at Penn is ideal to develop the applicant as a mentor and to foster the academic growth of mentees in these areas. Pulmonary arterial hypertension occurs in 4-8% of patients with portal hypertension (termed portopulmonary hypertension (PPHTN)). PPHTN has no known disease mechanism, limited, non-specific therapies, and may greatly complicate, delay, or prevent liver transplantation. Hepatopulmonary syndrome (HPS) is characterized by pulmonary microvascular dilations and impaired gas exchange and is found in up to 30% of patients being evaluated for liver transplantation. The mechanism for the development of HPS is similarly cryptic. Dr. Kawut recently performed a NIH-funded study focused on the clinical and genetic determinants of PPHTN and HPS. These studies showed that 1) female gender was a strong risk factor for PPHTN, 2) genetic variation in estrogen receptor β was associated with the occurrence of HPS , and 3) genetic variation in aromatase was associated with both higher plasma estradiol (E2) levels and a higher risk of PPHTN. These data strongly suggest estrogen as a potential therapeutic target in treatment and prevention of these pulmonary vascular sequelae of portal hypertension. Anastrozole (AN) is an FDA-approved aromatase inhibitor which dramatically decreases peripheral estrogen production in men and post-menopausal women. We therefore propose to conduct two ¿proof-ofprinciple¿ randomized clinical trials (RCTs) to begin the study of estrogen inhibition with AN for the treatment of PPHTN and HPS. We aim: 1) To determine the effects of AN versus placebo over three months in patients with PPHTN and 2) To determine the effects of AN versus placebo over three months in patients with HPS. End points will include E2 levels, transthoracic echocardiology measures, alveolar-arterial oxygen gradient, functional status, safety, and tolerability. If suggestive of benefit, the results could be used to plan and power multicenter Phase II or III RCTs of AN in one or both of these PVDs. This research would provide the ideal training ground for young investigators interested in POR in PVD who wish to study novel therapeutics for ¿orphan¿ diseases.

Steven M. Kawut，医学博士，医学硕士，芝加哥大学医学和流行病学副教授